ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1049G>A (p.Arg350Gln)

gnomAD frequency: 0.00002  dbSNP: rs875989914
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000850045 SCV004022404 uncertain significance Hypercholesterolemia, familial, 1 2023-04-28 reviewed by expert panel curation NM_000527.5(LDLR):c.1049G>A (p.Arg350Gln) variant is classified as Uncertain significance - conflicting evidence, for Familial Hypercholesterolemia by applying evidence codes PM2, BP4, BS3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: . PM2: PopMax MAF = 0.0001157 (0.01%) in Latino/Admixed Americans exomes+genomes (gnomAD v2.1.1). . BP4: REVEL = 0.373. it is below 0.50, so splicing evaluation is required. Functional data on splicing not available. A) Variant not on limits. B) Variant does not create GT. Variant is predicted not to alter splicing. . BS3: Level 1 assays: PMID 31106925 Heterologous cells (CHO), FACS assays - result - 100% LDLR expression, binding, and uptake . PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN>=6/ from PMID 31106925, after alternative causes of high cholesterol were excluded.
Color Diagnostics, LLC DBA Color Health RCV003581734 SCV004358505 uncertain significance Familial hypercholesterolemia 2023-04-10 criteria provided, single submitter clinical testing This missense variant (also known as p.Arg329Gln in the mature protein) replaces arginine with glutamine at codon 350 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study using transfected CHO cells has shown that this variant does not inhibit LDLR expression and LDL uptake (PMID: 31106925). This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 31106925). This variant has been identified in 4/250736 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg350Pro, is considered to be disease-causing (ClinVar variation ID: 226343), suggesting that arginine at this position is important for LDLR protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health RCV000850045 SCV004842640 uncertain significance Hypercholesterolemia, familial, 1 2023-12-07 criteria provided, single submitter clinical testing
Department of Genetics of Metabolic Diseases, Institute of Medical & Molecular Genetics, Hospital Universitario Hospital La Paz RCV000850045 SCV000992184 pathogenic Hypercholesterolemia, familial, 1 2019-01-01 no assertion criteria provided clinical testing

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